ABSTRACT Regenerative medicine therapies seek to replace cells or pathological tissues with engineered substitutes, but robust methods for precisely orchestrating activities of transplanted cells do not exist. This is especially true in pathological conditions that arise from chronic diseases, in which normal homeostatic and regenerative cues are overridden by deleterious signals, leading to cell death and loss of organ function. The goal of this proposal is to develop technologies that couple highly specific interactions between stem cells and their environments with programmed cellular outputs, such as homing, differentiation, matrix synthesis, and cytokine / growth factor secretion. We have developed a synthetic receptor platform that allows cells to recognize ligands through specificity imparted by carefully selected single chain variable fragments (scFv). Upon engagement of immobilized ligand (either membrane- or substrate-tethered) by this scFv receptor, engineered cells deploy a pre-defined program that dictates the outcome of cell-cell or cell-matrix interactions. Though we have used this platform to drive various behaviors in other cell types, we have not established its utility for guiding stem cell functions that are pertinent to regenerative medicine. We hypothesize that this synthetic sensory platform can enable stem cells to autonomously implement regenerative programs, such as homing, differentiation, or matrix synthesis, in response to cell-cell and cell-biomaterial interactions. In Specific Aim 1, we will establish our ability to link specific external signals to defined changes in stem cell states, including migration, differentiation, and extracellular matrix synthesis. In Specific Aim 2, we will incorporate ligands recognized by our synthetic receptors into biomaterial scaffolds. In this way, we will produce cellular delivery vehicles and tissue engineering scaffolds that enable the cells to self-select programmed behaviors with engineered, context-dependent specificity and precision. By implementing this novel sense and response system in regenerative medicine strategies, we intend to produce stem cell therapies capable of autonomously detecting features of a microenvironment and responding with a coordinated regenerative program that restores function, even in the absence of cues normally required for cell-based repair. This fellowship will provide me with the experience and tools critical for my goal of developing into a productive, independent scientist while also contributing key insights toward stem cell-based and biomaterial-guided tissue regeneration and repair.